Genetic Polymorphisms in ZFHX3 Are Associated with

Atrial Fibrillation in a Chinese Han Population

Yaowu Liu1., Bixian Ni2., Yuan Lin2, Xin-guang Chen1, Zhen Fang1, Liyan Zhao1, Zhibin Hu2*,
Fengxiang Zhang1*
1 Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China, 2 Department of Epidemiology and Biostatistics, School of
Public Health, Nanjing Medical University, Nanjing, Jiangsu, China

Abstract
Background: The gene zinc finger homeobox 3 (ZFHX3) encodes a transcription factor with cardiac expression and its
genetic variants are associated with atrial fibrillation (AF). We aimed to explore the associations between single nucleotide
polymorphisms (SNPs) of ZFHX3 and the risk of AF in a Chinese Han population.

Methods: We genotyped eight SNPs, including seven potentially functional SNPs and one previously reported SNP by using
the middle-throughput iPLEX Sequenom MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were
calculated in logistic regression models.

Results: We enrolled a total of 1,593 Chinese Han origin individuals in the study, including 597 AF patients and 996 non-AF
controls. Logistic regression analyses revealed that potentially functional SNPs rs6499600 and rs16971436 were associated
with a decreased risk of AF (adjusted OR = 0.73, 95% CI: 0.630.86, P = 1.0761024; adjusted OR = 0.74, 95% CI: 0.560.98,
P = 0.039, respectively). In addition, rs2106261 showed a robust association with an increased risk of AF (adjusted OR = 1.71,
95% CI: 1.462.00, P = 1.85610211). After multiple comparisons, rs16971436 conferred a borderline significant association
with the risk of AF. Stratification analysis indicated that the risks of AF were statistically different among subgroups of age
for rs2106261, and the effect for rs16971436 was more evident in subgroups of patients with coronary artery disease.

Conclusion: In summary, our study investigated the role of genetic variants of ZFHX3 in AF and two SNPs (rs2106261,
rs6499600) showed significant associations while rs16971436 conferred a borderline significant association with AF risk in
Chinese Han populations. However, further large and functional studies are warranted to confirm our findings.

Citation: Liu Y, Ni B, Lin Y, Chen X-g, Fang Z, et al. (2014) Genetic Polymorphisms in ZFHX3 Are Associated with Atrial Fibrillation in a Chinese Han
Population. PLoS ONE 9(7): e101318. doi:10.1371/journal.pone.0101318
Editor: Xun Ai, Loyola University Chicago, United States of America
Received February 23, 2014; Accepted June 4, 2014; Published July 1, 2014
Copyright: 2014 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by grants from the National Natural Science Foundation of China (Grant 81170160), the Program for Development of
Innovative Research Team in the First Affiliated Hospital of Nanjing Medical University (No. IRT-004), and the Six Peak Talents Foundation of Jiangsu Province
(No. 2011-WS-071). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* Email: zhibin_hu@njmu.edu.cn (ZH); njzfx6@163.com (FZ)
. These authors contributed equally to this work.

Introduction of AF patients were 1.77-fold to 4.67-fold more likely to have AF

Atrial fibrillation (AF) is the most prevalent sustained arrhyth-
mia in clinical practice characterized by uncoordinated atrial
activation. The prevalence of AF was estimated at approximately
2% of the general population [1,2] and this arrhythmia accounts
for nearly one-third of hospitalizations for cardiac rhythm
disturbances [3]. It is closely related to a 5-fold risk of stroke, a
3-fold incidence of congestive heart failure, and higher all-cause
mortality, which may contribute to high healthcare cost (average
2000 EUR per AF patient per year) [46].
AF frequently occurred coupled with multiple cardiovascular
risk factors such as advancing age, male sex, hypertension,
diabetes, ischemic, valvular heart disease, heart failure, and
hyperthyroidism [79]. However, some patients maintain sinus
rhythm regardless of various risk factors for AF while some other
patients develop AF without any evidence of AF-related diseases
[10]. Epidemiologic studies have shown that first-degree relatives
than the general population, and offspring with one parent
suffered from AF had approximately a 2-fold increase in the risk of
developing AF [11,12]. These facts indicate that predisposing
genetic factors may affect AF susceptibility. Over the past years,
lots of genetic studies of AF were performed by applying several
techniques such as linkage analysis, candidate gene resequencing
and association studies. Using these methods, especially genome
wide association studies (GWASs), investigators have identified
multiple genes and genetic loci which are associated with AF
[13,14]. In 2009, Benjamin et al. [15] conducted a meta-analysis
of GWASs for AF and identified a locus for AF (ZFHX3,
rs2106261, RR = 1.19; P = 2.761027). Candidate gene studies are
approaches employed by researchers to screen variants in any
gene that is hypothesized to cause a disease. We sought to identify
potentially functional AF susceptibility SNPs of ZFHX3 using the
candidate gene tool. Furthermore, we aim to confirm the

PLOS ONE | www.plosone.org 1 July 2014 | Volume 9 | Issue 7 | e101318


Table 1. Clinical characteristics in AF cases and AF-free controls.
Variants Cases (N = 597)
Male gender (%) 397(66.5%)
Age, years 58.4611.5
Paroxysmal AF (%) 383 (64.2%)
Persistent AF (%) 196 (32.8%)
Permanent AF (%) 18 (3.0%)
Lone AF (%) 71 (11.9%)
Hypertension (%) 260 (43.6%)
Diabetes (%) 53 (8.9%)
CAD (%) 48 (8.0%)
Data are presented as mean 6 standard deviation or number (percentage).
AF, atrial fibrillation; CAD, coronary artery disease; NA, not available.
doi:10.1371/journal.pone.0101318.t001
association of rs2106261 in ZFHX3 with AF risk in Chinese Han
populations.
Materials and Methods
Study population
This case-control study was approved by the Ethical Committee
Review Board of Nanjing Medical University, China. All the
participants enrolled in the study gave their written informed
consent.
In brief, the cases were incident AF patients recruited from
Department of Cardiology, the First Affiliated Hospital of Nanjing
Medical University from June 2010 to August 2013. All AF cases
in the study were confirmed according to the diagnostic criteria,
2011 ACCF/AHA/HRS focused updates incorporated into the
ACC/AHA/ESC 2006 guidelines for the management of patients
with atrial fibrillation [3]. Physical examinations were carried out
by expert cardiologists using routine 12-lead electrocardiography
(ECG), and/or ambulatory ECG recordings. According to clinical
characteristics, AF can be classified into paroxysmal AF (episodes
that generally last 7 days or less), persistent AF (episodes that
sustain beyond 7 days) and permanent AF (ongoing long-term
episodes, in which cardioversion has failed or has not been
attempted). Young AF individuals (under 60 years) without clinical
or echocardiographic evidence of cardiopulmonary disease,
including hypertension were considered as lone AF [16]. The
control subjects were genetically unrelated inpatient individuals
from multiple departments of the First Affiliated Hospital of
Nanjing Medical University. All the controls were confirmed to be
free of AF based on ECG or medical files at the time of
enrollment.
We also collected general and clinical information from medical
recording files in the hospital system such as age, gender, and
history of hypertension, diabetes, coronary artery disease (CAD),
and hyperthyroidism. Patients with hyperthyroidism, severe
cardiac dysfunction (NYHA Class IV) and advanced age (beyond
90 years) were excluded in both AF and control groups. All the
enrolled individuals are of the ethnic Chinese Han origin by self-
report.
SNP selection
We first used public HapMap SNP database (phase II + III Feb
09, on NCBI B36 assembly, dbSNP b126) to search SNPs that
localized within the gene region of ZFHX3 (including 10 kb up-
PLOS ONE | www.plosone.org
Polymorphisms in ZFHX3 and AF Risk
Controls (N = 996) P value
674(67.7%) 0.630
59.0610.2 0.278
NA -
NA -
NA -
NA -
267 (26.8%) ,0.001
28 (2.8%) ,0.001
51 (5.1%) 0.019
stream region of the gene), with MAF$0.05 in Chinese Han
population (CHB). Then, a web-based analysis tool was used to
predict the function of these SNPs (http://snpinfo.niehs.nih.gov/
snpinfo/snpfunc.htm). After function prediction analysis, a total of
9 potentially functional SNPs were selected. Using the Haploview
4.2 software, linkage disequilibrium (LD) analysis with an r2$0.8
was further applied to filter these functional SNPs and 7
(rs12596992, rs13336412, rs16971312, rs16971436, rs17680796,
rs6499600, rs8049936) of which were remained. Additionally,
previously reported single nucleotide polymorphism (SNP)
rs2106261 in ZFHX3 was selected as well for this study. As a
result, 8 loci were finally determined to perform genotyping.
SNP genotyping
Blood samples were drawn from study participants and genomic
DNA was isolated from EDTA-preserved whole blood, using the
standard phenol-chloroform method [17]. The genotyping was
performed by using the middle-throughput iPLEX Sequenom
MassARRAY platform (Sequenom, Inc, San Diego, CA, USA).
All SNPs were successfully genotyped with call rates .95%.
Statistical analysis
The standard independent samples t-test was used to compare
continuous variables and the x2 test was used to compare
categorical variables. The Hardy-Weinberg equilibrium compar-
ing the observed genotype frequencies with the expected ones was
determined by the x2 test in the control group. Odds ratios (ORs)
and 95% confidence intervals (CIs) were calculated using logistic
regression analyses in the additive model to assess the strength of
the associations between the variants genotypes and AF risk. The
heterogeneity of associations between subgroups was assessed
using the x2-based Q-test. All statistical analyses were performed
using STATA 12.0 software (Stata Corporation, College Station,
TX, USA) and P,0.05 was considered significant.
Results
Characteristics of the Study Population
A total of 1,593 Chinese Han origin individuals were recruited
in this study, including 597 AF patients and 996 non-AF controls.
The demographic characteristics of cases and controls are
summarized in Table 1. As shown, there were no significant
differences for the distributions of age and gender between cases
and controls (P values were 0.278 and 0.630, respectively). The
2 July 2014 | Volume 9 | Issue 7 | e101318
 Polymorphisms in ZFHX3 and AF Risk

mean age of AF and control groups was 58.4611.5 and

1.48610210
59.0610.2 years, respectively. Male proportion was 66.5% and

4.2861024
67.7% in AF group and control group, separately. Among cases,
PFDRc
64.2% patients were paroxysmal AF, 32.8% were persistent AF,

0.104
0.316
0.263
0.112

0.144

0.233
while others were permanent AF. And patients with lone AF
accounted for a small part (11.9%) of all AF cases. Considered as
common risk factors for AF, hypertension, diabetes, and CAD

211
1.0761024
were more prevalent in cases than controls (P,0.05).

1.85610

SNP, single nucleotide polymorphism; AF, atrial fibrillation; MAF, minor allele frequency; PHWE, P values for HardyWeinberg equilibrium tests in control groups; OR odds ratio; CI confidence interval.
0.039
0.316

0.056

0.175
0.23

0.09
Pb

Overall Associations between ZFHX3 Variants and AF risk

The genotype distributions of the 8 polymorphisms and their
associations with AF were shown in Table 2. The observed
0.74(0.560.98)

0.73(0.630.86)
1.71(1.462.00) genotype frequencies for these SNPs were all in agreement with
1.08(0.931.26)

0.85(0.721.00)

1.15(0.981.35)
b

1.1(0.941.27)

0.9(0.771.05) HardyWeinberg in the controls. Logistic regression analyses

OR(95%CI)

OR (95%CI) and P values were derived from logistic regression analysis in the additive model adjusting for age, gender, hypertension, diabetes and coronary artery disease.
revealed that functional SNPs rs6499600 and rs16971436 were
associated with decreased risks of AF in the additive model
(adjusted OR = 0.73, 95% CI: 0.630.86, P = 1.0761024; adjusted
OR = 0.74, 95% CI: 0.560.98, P = 0.039, respectively). In
addition, rs2106261 showed a robust association with an increased
PHWE

0.78
0.62
0.28
0.18
0.21
0.11
0.46
0.6

risk of AF (adjusted OR = 1.71, 95% CI: 1.462.00,

P = 1.85610211). We further calculated P values for false discovery
rate (P-FDR) to perform multiple comparisons. After comparisons,
we found that rs6499600 and rs2106261 remained their associ-
MAF(controls)

ations with AF risk while rs16971436 lost its association with the
risk of AF. There were no obvious evidences of significant
association between other 5 SNPs and AF risk.
0.37
0.45
0.29
0.09

0.42
0.32
0.33
0.3

Stratification Analysis
In the stratification analysis, we further evaluated the associa-
MAF(cases)

tions of rs6499600, rs16971436 and rs2106261 on AF risk in

subgroups based on age, gender, hypertension, diabetes and CAD.
As shown in Table 3, a significant difference among subgroups of
0.38
0.46
0.26
0.06
0.32
0.36
0.44
0.31

age was observed for the association of rs2106261 with AF risk (P

for heterogeneity = 0.001). Patients with CAD exhibited more
Table 2. Summary of associations between 8 SNPs in ZFHX3 and the risk of AF.

significant protective effect than patients who were free of CAD for
132/458/382
195/500/301

164/506/317

114/435/447
78/426/492
11/152/833
84/438/472

99/446/451
Controlsa

rs16971436 (adjusted OR = 0.13, 95% CI: 0.020.71).

Individuals homozygous for the minor allele/heterozygous/homozygous for the major allele.

Discussion
In this study, we investigated the associations between
polymorphisms of ZFHX3 and the risk of AF in a case-control
124/297/173

110/299/184
96/252/236

43/226/326

60/266/268
75/275/244

61/246/284

study including 597 cases and 996 controls. Seven potentially

3/71/523
Casesa

functional SNPs and one previously reported polymorphism in

ZFHX3 were selected for genotyping in our population. Two
SNPs (rs6499600 and rs2106261) were identified to be significantly
associated with AF risk and rs16971436 conferred a borderline
significant association with the risk of AF in Chinese Han
Minor/major allele

populations. Forrs2106261, the effects were statistically different

Multiple comparisons P values for false discovery rate.

among subgroups of age in stratified analysis, and the risk

associated with rs16971436 was more evident in patients with
CAD.
ZFHX3 (also known as ATBF1), encodes a transcription factor
G/A

A/G
G/A
C/G
A/C

G/T
T/C
T/C

with multiple homeodomains and zinc finger motifs, and regulates

doi:10.1371/journal.pone.0101318.t002

myogenic and neuronal differentiation. Little is known about the

function of ZFHX3 for cardiac expression, but it has been shown
71536544
71539450
71413345
71550264
71538441
71536875
71609121
71642787
Position

to interact with Protein Inhibitor of Activated Stat3 (PIAS3) [18].

STAT3 was found to be a regulator of paracrine circuits in the
heart, and it was essential for interstitial matrix deposition balance
and capillary vasculature maintenance [19]. Increased expression
of STAT3 has been observed in animal models of AF and
rs12596992
rs13336412
rs16971312
rs16971436
rs17680796

proposed to contribute to atrial matrix deposition. Tsai et al.

rs6499600
rs2106261
rs8049936

suggested that activated angiotensin II/Rac1/STAT may be

SNP

associated with or perhaps contribute to the structural and

b
a

inflammatory changes in AF [20].

PLOS ONE | www.plosone.org 3 July 2014 | Volume 9 | Issue 7 | e101318

 Table 3. Stratified analysis for associations of rs6499600, rs16971436 and rs2106261 in ZFHX3 with AF risk.

Adjusted Adjusted Adjusted

Variables Cases Controls OR(95%CI)a Pb Cases Controls OR(95%CI)a Pb Cases Controls OR(95%CI)a Pb

SNP rs6499600(TT/TC/CC) rs16971436(GG/GT/TT) rs2106261(AA/AG/GG)

Agec
#51 19/74/74 51/117/60 0.54(0.390.74) 0.099 0/22/146 1/34/196 0.83(0.461.50) 0.618 43/87/38 22/86/123 2.56(1.873.52) 0.001

PLOS ONE | www.plosone.org

52,60 20/74/63 48/151/92 0.75(0.551.01) 1/17/139 5/53/236 0.55(0.320.95) 37/68/52 26/126/142 2.00(1.492.69)
61,66 16/65/48 35/111/83 0.93(0.671.29) 1/13/115 1/27/202 0.90(0.471.73) 12/72/44 27/122/81 1.00(0.701.42)
$67 20/62/59 30/127/82 0.81(0.581.13) 1/19/123 4/38/199 0.83(0.471.46) 18/72/50 24/112/105 1.49(0.991.98)
Gender
Males 55/178/161 100/352/216 0.79(0.650.96) 0.131 1/45/351 7/107/560 0.65(0.450.93) 0.299 79/199/116 64/294/316 1.86(1.532.25) 0.070
Females 20/97/83 64/154/101 0.61(0.460.81) 2/26/172 4/45/273 0.92(0.571.47) 31/100/68 35/152/135 1.37(1.041.82)
Hypertension
Yes 36/130/94 37/140/86 0.91(0.701.19) 0.066 0/32/228 2/42/223 0.68(0.421.10) 0.687 44/129/87 17/126/124 1.78(1.352.34) 0.716
No 39/145/150 127/366/231 0.65(0.530.79) 3/39/295 9/110/610 0.77(0.551.10) 66/170/97 82/320/327 1.67(1.372.02)
Diabetes
Yes 7/27/19 7/13/8 0.70(0.301.66) 0.91 0/6/47 2000-3-25 1.62(0.279.63) 0.713 6/23/22 1/14/13 1.48(0.563.91) 0.764
No 68/248/225 157/493/309 0.74(0.630.87) 3/65/476 11/149/808 0.74(0.560.99) 104/276/162 98/432/438 1.74(1.482.04)

4
CAD
Yes 3/27/17 10/26/15 0.81(0.391.69) 0.579 0/2/46 0/10/41 0.13(0.020.71) 0.001 7/23/17 2/26/23 1.33(0.642.76) 0.486
No 72/248/227 154/480/302 0.74(0.630.88) 3/69/477 11/142/792 0.81(0.611.08) 103/276/167 97/420/428 1.72(1.462.03)

CAD, coronary artery disease.

a
Obtained in logistic regression models with adjustment for age, gender, hypertension, diabetes and coronary artery disease (the stratified factor in each stratum excluded).
b
P for heterogeneity test using the Chi-square-based Q test.
c
Age was divided into four sub-groups according to its median (60 years), lower quartile (51 years) and upper quartile (66 years).
doi:10.1371/journal.pone.0101318.t003
Polymorphisms in ZFHX3 and AF Risk

July 2014 | Volume 9 | Issue 7 | e101318


A total of 3 SNPs were significantly associated with the risk of
AF (rs2106261, rs6499600 and rs16971436) in our population.
The SNP rs2106261 locates in the first intron of ZFHX3 and has
been reported to confer increased risk of AF in European and
Chinese populations [15,21]. Even though the mechanism of
rs2106261 conferred increased susceptibility of AF is little known,
one plausible hypothesis is that it may alter the expression of
ZFHX3 by modulating regulation of ZFHX3 transcription or pre-
mRNA splicing because intronic sequences have been found to
play regulatory roles in gene expression recently [22]. The SNP
rs6499600 is located in the seventh intron of ZFHX3. And it may
affect the binding of transcription factors such as ATF6 (activating
transcription factor 6), which was predicted by the online tool
SNPinfo (http://snpinfo.niehs.nih.gov/index.html). ATF6 is a key
transcriptional activator to maintain cellular homeostasis, and
inhibition of which induced dilatation of left ventricle and
depression of cardiac function in murine heart [23]. ZFHX3
rs16971436 is a T to G variant at the codon of 428 of exon 1,
resulting in an amino acid alteration from threonine (Thy) to
proline (Pro). Therefore, we proposed that the missense variant
might lead to the change of ZFHX3 expression, consequently
cause a dysregulation of STAT3 and finally result in altered
susceptibility of AF.
Several limitations of the present study need to be addressed.
Firstly, we did not replicate the results in additional individuals,
this may contribute to potential false positive errors. The present
References
1. Stefansdottir H, Aspelund T, Gudnason V, Arnar DO (2011) Trends in the
incidence and prevalence of atrial fibrillation in Iceland and future projections.
Europace 13: 11101117.
2. Wilke T, Groth A, Mueller S, Pfannkuche M, Verheyen F, et al. (2013)
Incidence and prevalence of atrial fibrillation: an analysis based on 8.3 million
patients. Europace 15: 486493.
3. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, et al. (2011) 2011
ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC
2006 Guidelines for the management of patients with atrial fibrillation: a report
of the American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines developed in partnership with the European
Society of Cardiology and in collaboration with the European Heart Rhythm
Association and the Heart Rhythm Society. J Am Coll Cardiol 57: e101198.
4. Camm AJ, Lip GYH, De Caterina R, Savelieva I, Atar D, et al. (2012) 2012
focused update of the ESC Guidelines for the management of atrial fibrillation
An update of the 2010 ESC Guidelines for the management of atrial fibrillation
Developed with the special contribution of the European Heart Rhythm
Association. Europace 14: 13851413.
5. Benjamin EJ, Wolf PA, DAgostino RB, Silbershatz H, Kannel WB, et al. (1998)
Impact of atrial fibrillation on the risk of death: the Framingham Heart Study.
Circulation 98: 946952.
6. Ringborg A, Nieuwlaat R, Lindgren P, Jonsson B, Fidan D, et al. (2008) Costs of
atrial fibrillation in five European countries: results from the Euro Heart Survey
on atrial fibrillation. Europace 10: 403411.
7. Kannel WB, Abbott RD, Savage DD, McNamara PM (1982) Epidemiologic
features of chronic atrial fibrillation: the Framingham study. N Engl J Med 306:
10181022.
8. Benjamin EJ, Levy D, Vaziri SM, DAgostino RB, Belanger AJ, et al. (1994)
Independent risk factors for atrial fibrillation in a population-based cohort. The
Framingham Heart Study. JAMA 271: 840844.
9. Psaty BM, Manolio TA, Kuller LH, Kronmal RA, Cushman M, et al. (1997)
Incidence of and risk factors for atrial fibrillation in older adults. Circulation 96:
24552461.
10. Kopecky SL, Gersh BJ, McGoon MD, Whisnant JP, Holmes DR Jr, et al. (1987)
The natural history of lone atrial fibrillation. A population-based study over
three decades. N Engl J Med 317: 669674.
11. Arnar DO, Thorvaldsson S, Manolio TA, Thorgeirsson G, Kristjansson K, et al.
(2006) Familial aggregation of atrial fibrillation in Iceland. Eur Heart J 27: 708
712.
PLOS ONE | www.plosone.org
Polymorphisms in ZFHX3 and AF Risk
analysis was restricted to individuals of Chinese Han descent, and
therefore, the findings may not be generalizable to individuals of
other races and ethnicities. Secondly, as echocardiography results
were unable to be obtained from every participant, left ventricular
ejection fraction (LVEF) values were not measured to evaluate
cardiac function in both groups. Also, we did not analyze the
impact of SNPs on stroke because some patients enrolled in the
study had not performed head CT or MRI scans. Furthermore,
the way to select potentially functional SNPs as target ones by
using web-based tool may bring some positive or negative errors.
Therefore, the results are required to be further replicated by well-
designed studies in additional large-scale Chinese Han popula-
tions.
In conclusion, our study investigated the role of genetic variants
of ZFHX3 in AF and two SNPs (rs2106261, rs6499600) showed
significant associations while rs16971436 conferred a borderline
significant association with AF risk in Chinese Han populations.
However, further large and functional studies are warranted to
confirm our findings.
Author Contributions
Conceived and designed the experiments: FZ ZH. Performed the
experiments: Y. Liu BN Y. Lin ZF LZ. Analyzed the data: Y. Liu.
Contributed reagents/materials/analysis tools: BN XC. Wrote the paper:
Y. Liu BN FZ ZH.
12. Fox CS, Parise H, DAgostino RB Sr, Lloyd-Jones DM, Vasan RS, et al. (2004)
Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA
291: 28512855.
13. Lubitz SA, Yi BA, Ellinor PT (2010) Genetics of atrial fibrillation. Heart Fail
Clin 6: 239247.
14. Sinner MF, Ellinor PT, Meitinger T, Benjamin EJ, Kaab S (2011) Genome-wide
association studies of atrial fibrillation: past, present, and future. Cardiovasc Res
89: 701709.
15. Benjamin EJ, Rice KM, Arking DE, Pfeufer A, van Noord C, et al. (2009)
Variants in ZFHX3 are associated with atrial fibrillation in individuals of
European ancestry. Nat Genet 41: 879881.
16. European Heart Rhythm A, European Association for Cardio-Thoracic S,
Camm AJ, Kirchhof P, Lip GY, et al. (2010) Guidelines for the management of
atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the
European Society of Cardiology (ESC). Eur Heart J 31: 23692429.
17. Albarino CG, Romanowski V (1994) Phenol extraction revisited: a rapid method
for the isolation and preservation of human genomic DNA from whole blood.
Mol Cell Probes 8: 423427.
18. Nojiri S, Joh T, Miura Y, Sakata N, Nomura T, et al. (2004) ATBF1 enhances
the suppression of STAT3 signaling by interaction with PIAS3. Biochem
Biophys Res Commun 314: 97103.
19. Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, et al. (2004)
Signal transducer and activator of transcription 3 is required for myocardial
capillary growth, control of interstitial matrix deposition, and heart protection
from ischemic injury. Circ Res 95: 187195.
20. Tsai CT, Lin JL, Lai LP, Lin CS, Huang SK (2008) Membrane translocation of
small GTPase Rac1 and activation of STAT1 and STAT3 in pacing-induced
sustained atrial fibrillation. Heart Rhythm 5: 12851293.
21. Li C, Wang F, Yang Y, Fu F, Xu C, et al. (2011) Significant association of SNP
rs2106261 in the ZFHX3 gene with atrial fibrillation in a Chinese Han GeneID
population. Hum Genet 129: 239246.
22. Greenwood TA, Kelsoe JR (2003) Promoter and intronic variants affect the
transcriptional regulation of the human dopamine transporter gene. Genomics
82: 511520.
23. Toko H, Takahashi H, Kayama Y, Okada S, Minamino T, et al. (2010) ATF6 is
important under both pathological and physiological states in the heart. J Mol
Cell Cardiol 49: 113120.
5 July 2014 | Volume 9 | Issue 7 | e101318